CREPT/RPRD1B associates with Aurora B to regulate Cyclin B1 expression for accelerating the G2/M transition in gastric cancer

Lidan Ding,Danhui Ma,Yuqi He,Quentin Liu,Yanfang Ju,Jun Li,Yinyin Wang,Sihan Liu,Zhijie Chang,Yanshen Kuang,Bingtao Zhu,Mengdi Li,Xuanzi Fan,Baoqing Jia,Wanli Zhai,Liu Yang,Jianqiu Sheng,Fangli Ren

doi:10.1038/s41419-018-1211-8

Abstract

Gastric cancer, like most of other cancers, has an uncontrolled cell cycle regulated by cyclins and cyclin-dependent kinases (CDKs). In this study, we reported that gastric cancer cells showed an accelerated G2/M transition promoted by CREPT/RPRD1B and Aurora kinase B (Aurora B). We found that CREPT/RPRD1B and Aurora B were coordinately expressed during the cell cycle in gastric cancer cells. Deletion of CREPT/RPRD1B disturbed the cell progression and extended the length of cell cycle, leading to a significant accumulation of mitotic cells. Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1, which is critical for the regulation of gastric tumorigenesis. Our study provides a mechanism by which gastric tumor cells maintain their high proliferation rate via coordination of Aurora B and CREPT/RPRD1B on the expression of Cyclin B1. Targeting the interaction of Aurora B and CREPT/RPRD1B might be a strategy for anti-gastric cancer therapy in the future.

Highlights

Gastric cancer cells show a dysfunctional cell cycle controlled by cyclin-dependent kinases (CDKs) and related cyclins[1]
A cell proliferation experiment showed that cells overexpressing CREPT grew faster than the control cells, whereas cells transfected with a mixture of small interfering RNAs (siRNAs) against CREPT (Figure S1b) proliferated slowly comparing to the cells transfected with a scramble siRNA (Fig. 1a)
These results suggest that CREPT promotes cell proliferation, colony formation, and tumor growth in gastric cancer cells

Summary

Introduction

Gastric cancer cells show a dysfunctional cell cycle controlled by cyclin-dependent kinases (CDKs) and related cyclins[1]. Mutations and deregulations of genes encoding CDKs and cyclins result in gastric cell cycle dysfunction[2,3,4,5,6]. In both normal and tumor cells, different cyclins and CDKs are activated in different phases during their cell cycles. Our group reported that CREPT (cell cyclerelated and expression-elevated protein in tumor), named RPRD1B (regulation of nuclear pre-mRNA domain containing protein 1B), promotes cell proliferation and tumor development by altering cell cycle[16]. We have identified that CREPT/RPRD1B regulates the Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion